Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1998-06-24
2001-03-06
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S181000, C540S067000, C540S070000, C540S071000, C549S475000
Reexamination Certificate
active
06197761
ABSTRACT:
This application is a national stage entry under 35 U.S.C. §371 of PCT/GB96/03140, filed Dec. 19, 1996.
The present invention relates to novel anti-inflammatory and anti-allergic compounds of the androstane series and to processes for their preparation. The present invention also relates to pharmaceutical formulations containing the compounds and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.
Glucocorticosteroids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. However, glucocorticosteroids in general may suffer from the disadvantage of causing unwanted systemic effects following administration. WO94113690, WO94/14834, WO92/13873 and WO92/13872 all disclose glucocorticosteroids which are alleged to possess anti-inflammatory activity coupled with reduced systemic potency.
The present invention provides a novel group of compounds which possess useful anti-inflammatory activity whilst having little or no systemic activity. Thus, the compounds of the present invention represent a safer alternative to those known glucocorticoids which have poor side-effect profiles.
Thus, according to one aspect of the invention, there is provided a compound of formula (I)
and solvates thereof, in which
R
1
represents O, S or NH;
R
2
individually represents OC(═O)C
1-6
alkyl;
R
3
individually represents hydrogen, methyl (which may be in either the &agr; or &bgr; configuration) or ═CH
2
;
or R
2
and R
3
together represent
wherein R
6
and R
7
are the same or different and each represents hydrogen or C
1-6
alkyl;
R
4
and R
5
are the same or different and each represents hydrogen or halogen; and
represents a single or a double bond.
In the above definitions, the term “alkyl” as a group or part of a group means a straight chain, or, where available, a branched chain alkyl moiety. For example, it may represent a C
1-4
alkyl function as represented by methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.
The solvates may, for example, be hydrates.
References hereinafter to a compound according to the invention includes both compounds of formula (I) and solvates thereof, particularly pharmaceutically acceptable solvates.
It will be appreciated that the invention includes within its scope all stereoisomers of the compounds of formula (I) and mixtures thereof.
In particular the compounds of formula (I) contain an asymmetric centre at the point of attachment of the lactone moiety. Thus, the invention includes within its scope both diastereoisomers at this asymmetric centre and mixtures thereof.
Diastereoisomers and mixtures thereof at the asymmetric centre formed when R
2
and R
3
together represent
and R
6
and R
7
are different are also included within the scope of the present invention.
R
1
can be bonded to the alpha, beta or gamma carbon atoms of the lactone group,
however, compounds of formula (I) in which R
1
is bonded to the alpha atom are generally preferred.
A preferred group of compounds of the invention are compounds of formula (I) in which R
1
represents O or S, especially S.
A further preferred group of compounds of the invention are compounds of formula (I) in which R
2
individually represents OC(═O)C
1-6
alkyl, more preferably OC(═O)C
1-3
alkyl, especially OC(═O)ethyl. Compounds within this group in which R
3
is methyl are generally preferred.
Another preferred group of compounds are compounds of formula (I) in which R
2
and R
3
together represent
wherein R
6
and R
7
are the same or different and each represents hydrogen or C
1-6
alkyl, particularly hydrogen or C
1-3
alkyl, especially hydrogen, methyl or n-propyl.
Compounds of formula (I) in which R
4
and R
5
, which can be the same or different, each represents hydrogen, fluorine or chlorine, particularly hydrogen or fluorine, are preferred. Especially preferred are compounds in which both R
4
and R
5
are fluorine.
A particularly preferred group of compounds of the present invention are compounds of formula (I) in which R
1
is S; R
2
is OC(═O)C
1-6
alkyl, particularly OC(═O)C
1-3
alkyl, especially OC(═O)ethyl; R
3
is methyl; R
4
and R
5
, which can be the same or different, each represents hydrogen or fluorine, especially fluorine, and
represents a single or a double bond.
A further particularly preferred group of compounds of the invention are compounds of formula (I) in which R
1
is S; R
2
and R
3
together represent
wherein R
6
and R
7
are the same or different and each represents hydrogen or C
1-6
alkyl, particularly hydrogen or C
1-3
alkyl, especially hydrogen, methyl or n-propyl; R
4
and R
5
which can be the same or different each represents hydrogen or fluorine, especially fluorine; and
represents a single or a double bond. The R-isomers of compounds within this group in which R
6
and R
7
are different are preferred.
It is to be understood that the present invention covers all combinations of particularly and preferred groups referred to hereinabove.
Compounds of formula (I) include:
17&agr;-Butyryloxy-6&agr;,9&agr;-difluoro-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester;
17&agr;-Acetyloxy-6&agr;,9&bgr;-difluoro-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester;
9&agr;-Fluoro-11&bgr;-hydroxy-16&bgr;-methyl-3-oxo-17&agr;-propionyloxy-androsta-1,4-diene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester;
6&agr;,9&bgr;-Difluoro-11&bgr;-droxy-16&agr;-methyl-3-oxo-17&agr;-propionyloxy-androsta-1,4-diene-17&bgr;-carbothioic acid S-(5-oxo-tetrahydro-furan-2-yl) ester;
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-17&agr;-propionyloxy-androsta-1,4-diene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-4-yl) ester;
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-17&agr;-propionyloxy-androsta-1,4-diene-17&bgr;-carboxylic acid (2-oxo-tetrahydro-furan-3-yl) ester;
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-17&agr;-propionyloxy-androsta-1,4-diene-17&bgr;-carboxylic acid (2-oxo-tetrahydro-furan-5-yl) ester;
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;,17&agr;-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-5-yl) ester;
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;,17&agr;-isopropylidenedioxy-3-oxo-androst-4-ene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester;
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;,17&agr;-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17&bgr;-carboxylic acid N-(2-oxo-tetrahydro-furan-3-yl) amide;
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;,17&agr;-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17&bgr;-carboxylic acid (2-oxo-tetrahydro-furan-3-yl) ester;
16&agr;,17&agr;-Butylidenedioxy-11&bgr;-hydroxy-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester;
16&agr;,17&agr;-(R-Butylidenedioxy)-6&agr;,9&agr;-difluoro-11&bgr;-hydroxy-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester,
16&agr;,17&agr;-Butylidenedioxy-11&bgr;-hydroxy-3-oxo-androsta-1,4-diene-17&bgr;-carboxylic acid (2-oxo-tetrahydro-furan-3-yl) ester;
16&agr;,17&agr;-(R-Butylidenedioxy)-6&agr;,9&agr;-difluoro-11&bgr;-hydroxy-3-oxo-androst-4-ene-17&bgr;-carboxylic acid N-(2-oxo-tetrahydro-furan-3-yl) amide;
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;,17&agr;-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17&bgr;-carboxylic acid N-(2-oxo-tetrahydro-furan-4-yl) amide;
16&agr;,17&agr;-(R-Butylidenedioxy)-6&agr;,9&agr;-difluoro-11&bgr;-hydroxy-3-oxo-androst-4-ene-17&bgr;-carbothioic acid (5-oxo-tetrahydro-furan-2-yl) ester; and solvates thereof.
Preferred compounds of formula (I) include:
6&agr;,9&agr;-Difluoro-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-17&agr;-propionyloxy-androsta-1,4-diene-17&bgr;-carbothioic acid S-(2-oxo-tetrahydro-furan-3-yl) ester;
6&agr;,9&agr;-Difluoro-11&bgr;-h
Biggadike Keith
Procopiou Panayiotis Alexandrou
Coleman Brenda
Glaxo Wellcome Inc.
Nixon & Vanderhye
Shah Mukund J.
LandOfFree
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